gold(1+);(2S,3R,4R,5S,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxane-2-thiolate;triethylphosphanium | 34031-32-8

• 物质功能分类: 原料药 - 解热镇痛药 - 非甾抗炎药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: gold(1+);(2S,3R,4R,5S,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxane-2-thiolate;triethylphosphanium
• CAS: 34031-32-8
• 化学式: C20H35AuO9PS+
• 分子量: 679.5
• InChiKey: AUJRCFUBUPVWSZ-BQWBZISASA-N

物化性质

• 熔点：
  112-115°
• 溶解度：
  二甲基亚砜：≥5mg/mL
• 颜色/状态：
  White crystalline powder
• 气味：
  Odorless
• 稳定性/保质期：

  Auranofin powder darkens slightly when exposed to strong light and also to some extent when stored at a temperature of 60 °C or warmer; the darkening indicates a small degree of chemical degradation, but the effect on biologic activity is not known.

计算性质

• 辛醇/水分配系数(LogP)：
  1.87
• 重原子数：
  32
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  115
• 氢给体数：
  0
• 氢受体数：
  10

ADMET

代谢

代谢如此迅速，以至于在血液中未检测到完整的分子。

Metabolized so rapidly that the intact molecule has not been detected in blood.

来源:Hazardous Substances Data Bank (HSDB)

代谢

接受金钠硫代硫酸盐治疗的病人尿中的主要金物种是[Au(CN)2]-，这也见于血液中的低分子量浸润。服用金诺芬的病人的尿液和血液中也发现了同样的化合物。

For a patient receiving gold sodium thiomalate the principal gold species in the urine is [Au(CN)2]-, which is also seen in a low molecular weight infiltrate of the blood. The same compound is also identified in the urine and blood of a patient taking auranofin

来源:Hazardous Substances Data Bank (HSDB)

代谢

金诺芬（Auranofin），2,3,4,6-四-O-乙酰-1-硫-β-D-吡喃葡萄糖苷-S-（三乙基膦）-金(I)，在与仓鼠或大鼠肠道壁接触时被代谢，产生去乙酰化形式的药物。这个产物，1-硫-β-D-吡喃葡萄糖苷-S-（三乙基膦）-金(I)，在仓鼠或大鼠肠道反转实验中穿过了肠道壁...

Auranofin, 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-(triethylphosphine)- gold(I), ...metabolized in contact with hamster or rat gut wall to yield the deacetylated form of the drug. This product, 1-thio-beta-D-glucopyranosato-S-(triethylphosphine)-gold(I), passed through hamster or rat intestinal wall in an everted gut experiment...

来源:Hazardous Substances Data Bank (HSDB)

代谢

从红细胞（RBCs）中流出的金，暴露于10-100微摩尔奥罗诺芬，三乙磷(2,3,4,6-四-O-乙酰-1-β-D-葡萄糖苷酸-S-)金(I)进行了研究。全血中的红细胞被允许积累金，然后放入新鲜的血浆或缓冲盐水溶液中... [14C]谷胱甘肽，通过原位标记生成，也流出并与白蛋白和金结合，提供了第一个直接证据，表明白蛋白-金-谷胱甘肽复合物（AlbSAuSG）可能是奥罗诺芬的循环代谢物，在奥罗诺芬的两个原始配体都被取代后形成。

The efflux of gold from red blood cells (RBCs) exposed to 10-100 microM auranofin, triethylphosphine(2,3,4,6-tetra-O-acetyl- 1-beta-D-gludopyranosato-S-)gold(I) was studied. RBCs in whole blood were allowed to accumulate gold, and then were place in fresh plasma or buffered saline solution. ...[14C]Glutathione, generated by in situ labeling, also effluxed and associated with the albumin and gold, providing the first direct evidence that the albumin-gold-glutathione complex (AlbSAuSG) may be a circulating metabolite of auranofin formed after both of the original ligands of auranofin are displaced.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在使用金剂治疗期间出现皮疹似乎不会影响青霉胺治疗期间皮疹的发展，但曾在金剂治疗期间出现蛋白尿或骨髓抑制的患者可能会增加发展为类似副作用的风险。

...there may be a higher incidence of penicillamine toxicity in patients who have previously shown toxic reactions. The interval between stopping the gold and starting the penicillamine did not influence incidence of toxicity. The development of a rash during gold treatment does not seem to influence the development of a rash during penicillamine treatment, but patients who have had proteinuria or bone-marrow depression during gold treatment may have an increased likelihood of developing a similar side effect with penicillamine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在一篇单一病例报告中，有建议称同时使用Ridaura（金诺芬）和苯妥英可能增加了苯妥英的血药水平。

In a single-patient report, there is the suggestion that concurrent administration of Ridaura /auranofin/ and phenytoin may have increased phenytoin blood levels.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

尚无使用螯合剂等疗法治疗Ridaura（金诺芬）过量的经验。然而，它们已与可注射的金制剂一起使用，并可以考虑用于Ridaura（金诺芬）过量。

There has been no experience with treating Ridaura overdosage with modalities such as chelating agents. However, they have been used with injectable gold and may be considered for Ridaura /(auranofin)/ overdosage.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

在急性过量情况下，建议立即进行催吐或洗胃，并给予适当的支持性治疗。

In case of acute overdosage, immediate induction of emesis or gastric lavage and appropriate supportive therapy is recommended.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

与治疗类风湿性关节炎的金盐相关的肺毒性...如果正确处理，通过简单中断金盐治疗或使用皮质类固醇，预后良好，大多数情况下可以完全治愈。报告了一例对皮质类固醇治疗反应良好的病例，并分析了与类风湿性关节炎相关的肺纤维化的鉴别诊断。/金盐/

Pulmonary toxicity associated with gold salt treatment of rheumatoid arthritis...has a good prognosis if treated properly with the simple interruption of gold salts or with corticosteroids, with complete cure in the majority of cases. A case with good response to corticosteroid therapy is reported and the differential diagnosis with pulmonary fibrosis associated with rheumatoid arthritis is analyzed. /Gold salt/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在活体中，来自金诺芬的金大约有60%与血清蛋白结合。在与血清蛋白结合的金中，有82%与白蛋白结合，其余与α1-、α2-和β-球蛋白结合，可能还与IgG结合。血清中来自金诺芬的自由金的比例不到1-2%；使用金诺芬达到的自由金血清浓度似乎与使用金硫代酸钠达到的浓度相似。

In vivo, gold from auranofin is approximately 60% bound to serum proteins. Of the gold bound to serum proteins, 82% is bound to albumin and the remainder to alpha1-, alpha2-, and beta-globulins and possibly to IgG. Less than 1-2% of gold from auranofin in serum is present as free gold; serum concentrations of free gold attained with auranofin appear to be similar to those attained with gold sodium thiomalate.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在动物口服多剂量的金诺芬后，金元素在肾脏中的浓度最高；金也分布到脾脏、肺、肾上腺和肝脏，心脏、睾丸、消化道、肌肉、眼睛、脂肪和大脑中的浓度较低。在动物（可能在人类中也是如此），金诺芬中的少量金分布到胆汁中。类风湿性关节炎患者接受金诺芬治疗的关节滑液中的金浓度远低于接受parenteral金化合物治疗的患者，但在金诺芬治疗期间，血液与关节滑液中的金浓度比值与parenteral金治疗期间相似（大约1.7:1）。初步数据显示，在金诺芬治疗期间，皮肤中几乎没有或没有金积累，这与parenteral金化合物治疗期间发生的积累形成对比。在金诺芬治疗期间，头发或指甲几乎没有或没有金积累，并且到目前为止，即使总累积剂量高达6.1克，也未检测到角膜或晶状体中金的积累。

Following oral administration of multiple doses of auranofin in animals, gold is distributed in highest concentrations into the kidneys; gold is also distributed into the spleen, lungs, adrenals, and liver, with lower concentrations being distributed into the heart, testes, GI tract, muscle, eyes, fat, and brain. In animals (and possibly in humans), small amounts of gold from auranofin are distributed into bile. Synovial fluid gold concentrations in rheumatoid arthritis patients receiving auranofin are much lower than those in patients receiving therapy with parenteral gold compounds, but the ratio of blood-to-synovial fluid gold concentrations during auranofin therapy is similar to that during parenteral gold therapy (approximately 1.7:1). Preliminary data suggest that little or no gold cumulates in skin during auranofin therapy, in contrast to the accumulation that occurs during therapy with parenteral gold compounds. Little or no gold accumulation occurs in hair or nails during auranofin therapy, and accumulation of gold in the cornea or lens during therapy with the drug has not been detected to date with total cumulative doses as high as 6.1 g.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服单剂6毫克金诺芬后，健康成年人的平均血金峰浓度在2小时时为0.025微克/毫升（范围：0.014-0.046微克/毫升）。在类风湿性关节炎患者中，多次口服给药后，通常在8-12周内达到稳态血金浓度，尽管某些患者可能需要13-16周的时间。尽管个体间存在相当大的差异，但一旦在金诺芬治疗期间达到稳态血金浓度，继续给药时血金浓度的个体内差异似乎最小。

Following oral administration of a single 6-mg dose of auranofin in healthy adults, mean peak blood gold concentrations of 0.025 ug/mL (range: 0.014-0.046 ug/mL) occurred at 2 hours. Following oral administration of multiple doses of the drug in patients with rheumatoid arthritis, steady-state blood gold concentrations are usually attained after 8-12 weeks, although periods of 13-16 weeks may be necessary in some patients. While there appears to be considerable interindividual variation, once steady-state blood gold concentrations are attained during auranofin therapy, there appears to be minimal intraindividual variation in blood gold concentration with continued dosing.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

动物研究的结果表明，奥罗诺金的配体几乎被完全吸收；由于只有很小一部分的金被吸收，因此认为该药物在胃肠道内其配位键发生了广泛的断裂。一些实验数据表明，奥罗诺金可以松散且可逆地吸附在胃肠道粘膜上。其他实验数据表明，奥罗诺金的金含形态可能通过粘膜下吸收，可能的初始代谢过程是在胃肠道粘膜内发生脱乙酰化。

Results of animal studies indicate that the ligands of auranofin are almost completely absorbed; since a much smaller fraction of the gold is absorbed, the drug is believed to undergo extensive disruption at its coordination bonds within the GI tract. Some experimental data suggest that auranofin is loosely and reversibly adsorbed onto GI mucosa. Other experimental data suggest that gold-containing forms of auranofin may undergo transmucosal absorption, possibly with the initial metabolic process being deacetylation within the GI mucosa.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S36/37
• 危险类别码：
  R63,R22
• WGK Germany：
  3
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P261,P280,P301+P310,P305+P351+P338,P342+P311
• 危险品运输编号：
  2811
• 危险性描述：
  H301,H318,H334,H350,H360

制备方法与用途

金诺芬简介

金诺芬是一种抗风湿病的有机金化合物，即一种金制剂。它通过乙酰化的硫代葡糖在金原子和三乙基磷配位形成。在体内，首先金原子与硫原子结合，然后发生金原子和磷原子断键，从而发挥作用。

生物活性

Auranofin（Ridaura, SKF-39162）是 thioredoxin reductase (TrxR) 的抑制剂，在无细胞分析中对纯化的幽门螺杆菌 TrxR 的 IC50 值为 88 nM。在浓度为 1.2 μM 下，Auranofin 可以完全抑制细菌生长，并且是 FDA 批准的含金化合物，用于治疗类风湿关节炎。

靶点

Target	Value
TrxR (Cell-free assay)	88 nM

化学性质

金诺芬为无色结晶，熔点在110-111℃之间。其旋光度 [α]D23 = -55.3°（C=1，甲醇）。急性毒性 LD50：大鼠口服 265 mg/kg；小鼠口服 310 mg/kg。

用途

金诺芬是一种含金的口服抗风湿药，可能作用于嗜中性白细胞、单核细胞，提高细胞免疫和防御功能而起效。其特点是显效慢，一般需3～4个月开始显效。主要用于减缓类风湿性关节炎的骨质破坏。

生产方法

吡喃葡糖与乙酸成酯后选择性溴化得化合物(I)。2.0g 化合物(I)、1.2g 硫化钠(或相应的硫化钾)及 1.7g 三乙基膦氯化金，在氯仿-水混合液中，室温搅拌1小时，可得金诺芬。

制备三乙基膦氯化金

溶于25ml乙醇的10.0g (0.08mol) 的2,2’-二羟基二乙硫醚所成溶液和溶于75ml蒸馏水的15.76g(0.04mol) 氯化金酸三水合物所成溶液相混合。当橙黄色溶液变为几乎无色时，冷至-5℃，在搅拌下滴加入 -5℃ 的溶于25ml乙醇的5.0g (0.0425mol) 三乙基膦；加完后继续搅拌0.5小时。过滤出产生的固体后，滤液浓缩至约30ml以产生沉淀，过滤；2次过滤出的固体一起用水：乙醇(2:1) 来洗涤；溶于乙醇中，通过加入水至产生混浊后，任其结晶；得到白色针状三乙基膦氯化金，熔点85-86℃。

类别

有毒物品

性能与储运特性

• 毒性分级：高毒
• 急性毒性：口服 - 大鼠 LD50: 265 mg/kg；小鼠 LD50: 310 mg/kg
• 可燃性危险特性：可燃，燃烧时产生有毒氮氧化物和硫氧化物烟雾
• 病人用药副作用：胃出血和胃溃疡
• 储运特性：通风低温干燥存放，并与库房食品原料隔离
• 灭火剂：干粉、泡沫、沙土、二氧化碳、雾状水